Synthesis of vinyl esters

ABSTRACT

Vinyl ester of an alcohol (such as benzoin) is made by reaction of the alcohol with a 3-haloalkyl acid halide (such as 3-chloropropional chloride or bromide) in an anhydrous liquid reaction medium comprising an aprotic solvent (such as toluene) and a hydrogen halide acceptor (such as a tertiary amine) at a temperature of at least 20° C.

This invention relates to the synthesis of vinyl esters derived from analcohol which may be aliphatic or non-aliphatic (e.g., a phenol) and maybe polyhydric. The invention is of particular value when the alcohol issterically hindered due to the position of the hydroxyl group of thealcohol relative to a cyclic or other bulky group in the alcohol.

When the alcohol that is to provide the esterifying group is notsterically hindered (for instance when it is a straight chain aliphaticalcohol) it is relatively easy to form a vinyl ester by reaction of thealcohol with an ethylenically unsaturated carboxylic acid, for instanceusing an acidic catalyst. However this technique tends to be inadequatewhen the alcohol is sterically hindered.

One example of a valuable ester that is difficult to synthesise isbenzoin acrylate. The hydroxyl group in benzoin is sterically hinderedand the solubility of benzoin in many solvents is low. A synthesis ofbenzoin acrylate is described in Chemical Abstracts 40151K Volume 68 inwhich benzoin was dissolved in dimethyl aniline and chloroform andacryloyl chloride was added dropwise at below 10° C. The recoveryprocedures involve distillation under reduced pressure and the additionof aqueous sulphuric acid with ice cooling. The use of acryloyl chlorideas a reactant is undesirable because of difficulties associates with themanufacture, supply and storage of acryloyl chloride. For instance itsinitial synthesis is inconvenient to perform and the product tends to beunstable on storage.

A further disadvantage in the described process is that it requires theuse of chloroform as part of the reaction medium. This may result in theend product containing trace amounts of chloroform. For some purposes,e.g., pharmaceutical purposes, even trace amounts of halogenatedhydrocarbon impurities are considered undesirable.

Processes are described in JP-A-61/286346 and 61/286347 in which onemole of a particular sterically hindered alcohol is reacted with 0.9 to1.25 moles β chloropropionyl chloride per hydroxyl group at -10° to 35°C. in a polar organic solvent and in the presence of an aqueous solutionof sodium hydroxide or potassium hydroxide. Temperatures of 0° to 10° C.are said to be especially preferred. It is stated that if thetemperature is higher, there is hydrolysis of the chloropropionolchloride which causes a decline in yield, and there is hydrolysis of theend product.

Although the low temperatures are essential in this process for thereasons stated, they have undesirable disadvantages. The solubility ofthe alcohol at the low temperatures is less than it would be at highertemperatures. With alcohols such as benzoin, which tend to have arelatively low solubility in many solvents, the use of low temperaturesnecessarily limits the concentration of the alcohol that can bedissolved in the reaction mixture, and thus reduces the yield of vinylester that can be obtained from a given reaction vessel in a givenreaction time (the pot yield). Further, the use of a low temperaturenecessarily results in a lower reaction rate.

One important object of the invention is to provide a more convenientand reliable synthesis of benzoin acrylate.

Another object of the invention is to provide a convenient synthesis forvinyl esters of alcohols in general, especially sterically hinderedalcohols.

Another object is to provide such processes that can be performed in theabsence of halocarbons.

Another object to devise a process for making vinyl esters of alcoholsand which is convenient to perform and which is especially suitable forsterically hindered alcohols and which is capable of giving a good potyield of the desired product.

In the invention, we make a vinyl ester of an alcohol by reaction of thealcohol with a 3-haloalkyl acid halide in a liquid reaction medium inwhich the alcohol is dissolved and through which a hydrogen halideacceptor is distributed, and in this process the liquid reaction mediumis an anhydrous reaction medium and comprises aprotic solvent, and thereaction temperature is at least 20° C.

As a result of the reaction medium being anhydrous and comprising aaprotic solvent and the hydrogen halide acceptor it is possible toperform the reaction at sufficiently high temperature that evenrelatively insoluble alcohol such as benzoin can have reasonably highsolubility (e.g., at least 10%) and such that a satisfactory rate ofreaction is achieved. Accordingly it is possible, by the invention, toobtain a high pot yield rapidly with little or no by-product formation.

The reaction temperature is normally above 35° C. and most preferably itis above 40° C. The upper limit will generally depend on, for instance,the thermal stability of the alcohol and the vinyl ester, the boilingpoint of the solvent, and on the reaction apparatus that is being used.Generally the reaction temperature is below 90° C. For many reactions,temperatures in the range of 45° to 80° C. are convenient. Preferablythe reaction is conducted with reflux distillation of the solvent and sothe solvent and the reaction pressure (which is generally at or belowatmospheric) may be selected to give a suitable reflux and reactiontemperature.

It is essential that the reaction medium is anhydrous since the presenceof significant amounts of water will result in hydrolysis of the acidhalide group and in increased by-product formation. Preferably theamount of water in the reaction medium during the reaction is as low aspossible and should be substantially zero. However very small amounts,e.g., 1%, may be tolerated, but increasing the amount of water tends toincrease the amount of by-products. The haloalkyl acid halide can beused to dehydrate the reaction medium (with consequential and generallyundesirable formation of hydrolysis products) but generally each of thecomponents that is to be used in the reaction medium should besubstantially anhydrous. If any component is likely to be contaminatedwith moisture it is desirable to subject that component to a dehydrationprocess before introduction to the reaction, for example by exposure toa material that will remove water. This may be a material that willabsorb water reversibly but is preferably a scavenger that will reactirreversibly with water. Suitable scavengers are acid anhydrides, acidchlorides and, especially, phosphorous pentoxide.

In order to ensure the maintenance of anhydrous conditions throughoutthe reaction it is often preferred to include a water scavenger, such asphosphorous pentoxide, in the reaction medium.

The hydrogen halide acceptor may be any material that will absorbhydrogen halide liberated during the reaction, and in particular is amaterial that will promote the extraction of hydrogen halide from thestarting material or intermediate product, which is probably thehaloalkyl ester of the alcohol. The hydrogen halide acceptor must bedistributed throughout the reaction medium in order that it is readilyavailable to accept hydrogen halide as it is liberated. It can bepresent as finely dispersed solid material, for instance an inorganicbase such as sodium or potassium carbonate or bicarbonate, in whichevent the reaction with the hydrogen halide is a solid phase reaction.Preferably, however, the hydrogen halide acceptor is in solution in thereaction medium, and the reaction is a liquid phase reaction. Thepreferred hydrogen halide acceptors are tertiary amines where thenitrogen atom is substituted by three groups selected from aliphatic,cycloaliphatic, heterocyclic and aromatic groups, preferably a tertiaryalkylamine where each alkyl group contains 1 to 8 carbon atoms.Triethylamine is a suitable hydrogen halide acceptor. The acceptorshould be unreactive with the alcohol and the 3-haloalkyl acid halide.

The aprotic solvent can be any solvent that is free of a proton thatcould result in reaction between the solvent and the acid halide.Preferably it is a solvent of moderate polarity for instance having aHildebrand polarity of less than 0.6. It can be an ether (for instancetetrahydrofuran) or ketone (for instance acetone) but is preferably asolvent of low polarity, preferably a non-polar solvent. Although ahalogenated hydrocarbon such as dichloromethane can be used as part orall of the the solvent, it is preferred for the solvent and the reactionmedium to be free of halo carbons. Preferably the aprotic solvent is ahydrocarbon solvent. The hydrocarbon may be aliphatic, alicyclic oraromatic, especially a petroleum ether, paraffin, toluene or xylene.Preferably the reaction medium consists only of the defined solvent orsolvents and reactants, so that the defined aprotic solvent ispreferably the only solvent that is present in the reaction.

The amount of aprotic solvent will be selected having regard to thereaction temperature that is to be used and the solubility of thealcohol in the aprotic solvent. Generally the reaction temperature andsolvent are such that the alcohol has a solubility of at least 10% byweight in the solvent at the chosen reaction temperature (based on theweight of alcohol and the aprotic solvent) and so the amount of aproticsolvent will generally be below 10 parts by weight per part by weight ofthe alcohol. In order to maximise pot yield, the amount is generally aslow as is acceptable consistent with the solubility of the alcohol, andtypically is below 7 parts per part by weight alcohol. Generally it isabove 2 parts.

When the hydrogen halide acceptor is dissolved in the reaction medium,the concentration of the alcohol in the liquid phase of the reactionmedium is generally at least 8%, and preferably at least 12 or 15%(based on the weight of alcohol and liquid reaction medium) at thereaction temperature.

The proportions of alcohol and acid halide and hydrogen halide acceptorare preferably substantially stoichiometric. The amount of halo halideis generally from 0.8 to 2 moles per mole hydroxyl groups in thealcohol, with amounts of 1 to 1.4 moles being suitable. The amount ofhydrogen halide acceptor is generally from 2 to 3 moles per molehydroxyl groups in the alcohol, although greater amounts can be used.

The 3-haloalkyl acid halide is generally a compound of the formula CR₂ ¹XCHR² COY. The groups R¹ may be the same or different and can bealiphatic, heterocyclic or aromatic. For instance they can be C1-8alkyl, phenyl or benzyl. Preferably at least one group R¹, andfrequently each of the groups R¹, is hydrogen. R² can be methyl but isgenerally hydrogen. X and Y can be the same or different and may bechloro or bromo. The preferred compound has X and Y chloro and each R¹and R² hydrogen, namely 3-chloro propionyl chloride.

The alcohol is preferably a sterically hindered alcohol. Generally itcontains at least 4 carbon atoms and more usually at least 10 carbonatoms. It can be monohydric or polyhydric (e.g., a glycol or sugar) andit can be aliphatic, heterocyclic or aromatic (e.g., a phenol).

The alcohol can be selected from cyclic alcohols, as described below,tertiary alcohols as described below, and primary or secondary alcoholsas described below.

The cyclic alcohols are alcohols in which the hydroxyl group is bondedto a ring carbon atom. The ring may be aliphatic, aromatic orheterocyclic and generally contains 5 to 8 ring members or may be abicyclic or other polycyclic ring. The cyclic alcohol may include morethan one hydroxyl group. It may be a sugar.

The tertiary alcohols are alcohols in which the hydroxyl group is bondedto a tertiary carbon atom. This is substituted by three groups which areselected from aliphatic, aromatic and heterocyclic groups and whichgenerally provide, together, at least 4 and usually at least 10 carbonatoms.

The primary and secondary alcohols are alcohols wherein the hydroxylgroup is bonded to a carbon atom carrying one or two hydrogens andsubstituted by two or one aliphatic, aromatic or heterocyclic groupswherein at least one of the substituents comprises a tertiary carbonatom or a ring of at least five atoms wherein the tertiary carbon or thering is connected to the primary or secondary carbon by a direct bond orby a chain of up to three atoms.

When the alcohol is monohydric, it can be expressed as having theformula R³ OH in which event the vinyl ester will have the formula CR₂ ¹=CR² COOR³, but when the alcohol is dihydric having the formula HOR³ OHthe end product may be a compound having the formula CR₂ ¹ =CR² COOR³OOCCR² =CR₂ ¹ or it may be an unsymmetrical compound, for instancewherein one of the hydroxyl groups does not react.

For simplicity, in the following description we refer only to monohydricalcohols but it will be appreciated that dihydric or polyhydric alcoholscan be used.

The alcohol R³ OH is preferably a compound of the formula ##STR1##wherein R⁴, R⁵ and R⁶ are preferably as defined below, and R³ in thedesired end product therefore preferably is a group of the formula##STR2##

In the preferred cyclic alcohols R⁴ and R⁵ together with the carbonatoms to which they are attached provide a ring of at least 5 ring atomsthat may be aliphatic, heterocyclic or aromatic and R⁶ is hydrogen or analiphatic, aromatic or heterocyclic group or is absent if the ring isunsaturated. The ring may itself be a ring in a polycyclic compound, forinstance at least one other ring may be fused to it. Suitable examplesof cyclic alcohols of this type include 1 methyl cyclohexanol,substituted phenols, hydroxypyridine.

In the preferred tertiary alcohols, R⁴, R⁵ and R⁶ are each aliphatic,aromatic or heterocyclic. It is particularly preferred that at least oneof them should be a group R⁷ as defined below.

In preferred secondary alcohols, R⁶ is hydrogen, R⁵ is aliphatic,aromatic or heterocyclic and may be a group R⁷, and R⁴ is a group R⁷ asdefined below. In primary alcohols R⁵ and R⁶ are hydrogen and R⁴ is agroup R⁷ as defined below.

Groups R⁷ are groups of the formula ##STR3##

In these, Z is a direct bond or a chain of up to three chain members.These may be carbon (for instance methylene or carbonyl groups) oroxygen (ether linkages) or any other suitable linking groups. Preferablythere are only one or two chain members or a direct bond. R⁸ and R⁹together with the carbon or nitrogen atom to which they are attached mayform a ring of at least 5 ring atoms or R⁸ and R⁹ may both be aliphatic,aromatic or heterocyclic. In some instances, especially when Z is adirect bond or a single group such as methylene or carbonyl and R⁸ is abulky group such as a cyclic group, R⁹ may be hydrogen. R¹⁰ is absentwhen R⁸ and R⁹ form an aromatic ring with the carbon atom, but otherwiseR¹⁰ is generally aliphatic, aromatic or heterocyclic, but may behydrogen, especially when R⁸ and/or R⁹ are cyclic or other bulky groups.

Any of the aliphatic groups may be saturated or unsaturated such asalkyl or alkenyl. They may be linear or branched. They generally contain1 to 24 carbon atoms. Any of the aromatic groups may be wholly aromaticor may comprise aromatic groups substituted on to an aliphatic group andmay comprise aliphatic or other substituents on the aromatic group. Forinstance phenyl groups may be substituted on to methylene and/or may besubstituted by halo, alkyl or nitro. In heterocyclic groups, the heteroatoms may be, for instance, oxygen or nitrogen and the ring may containsufficient carbon atoms to make a 5- or 6-membered ring. This ring maybe fused to a carbocyclic or other ring. Any carbocyclic ring generallyhas 5- or 6-ring carbon atoms and may be fused to other rings.

Preferred alcohols are those in which R⁴, and optionally also R⁵, arerepresented by a group R⁷ wherein R⁸ and R⁹ and the carbon atom to whichthey are attached form an aromatic ring and R¹⁰ is absent, and Z iseither a direct bond or a carbonyl linkage or other suitable shortlinkage between the alcoholic carbon and the ring. Such a material isbenzoin.

Other examples of suitable alcohols are di- and triphenyl methanols and2,6-dimethyl-4-heptanol.

The reaction is typically conducted by forming the anhydrous liquidreaction medium of alcohol, aprotic solvent and hydrogen halide acceptorto the desired anhydrous state (e.g., by including a water scavenger orby, if necessary, contacting one or more of the materials with adehydration agent) and then adding the acid halide gradually to thereaction medium, with the reaction generally being at the desiredreaction temperature throughout the addition. Reaction is generallycontinued for a further period of at least quarter of an hour, e.g., 1to 5 hours, after the addition is completed. The addition may beconducted over a period of half an hour to eight hours. The reaction isgenerally continued until subtantially complete conversion is achieved.

After the reaction has been completed, the desired end product isrecovered. Recovery can be by filtration (for instance to remove solidphase hydrogen halide acceptor or amine hydrogen halide salt that is insolid state) but preferably the desired end product is recovered bycooling and adding sufficient water to dissolve the amine hydrogenhalide salt which can be decanted. The desired ester remains in theaprotic solvent. After washing the organic solution with water, thewater is preferably removed by azeotropic or other distillation, or bythe use of drying agents. The product can be recrystallised if necessaryby conventional techniques.

The following are examples Of the invention.

EXAMPLE 1

Benzoin (180 g), phosphorous pentoxide (4 g) and triethylamine (188 g)were stirred in dry toluene (970 g) and heated to 40° C. The3-chloropropionyl chloride (131 g) was added dropwise over 4 hours,keeping the temperature below 60° C. After addition was complete thereaction was continued for a further 3 hours and tehn allowedd to coolto ambient. Water (188 g) was added with stirring to dissolve thetriethylamine hydrochloride salt. The aqueous phase was separated andthe organic extract washed with water (80 g). The combined aqueouslayers were backwashed with toluene (167 g).

The combined organic phases were returned to the reaction flask andwater was removed by azeotropic distillation followed by removal of thesolvent under vacuum to leave 220 g (97.8%) of crude dark yellowproduct. Recrystallisation gave 169 g of a fine yellow powder.

EXAMPLE 2

This example demonstrates that alcohols can be acrylated by halogenatedpropionyl chlorides other than the chlorinated reagent. The procedure ofExample 1 is employed but using 3-bromopropionyl chloride, theconversion of benzoin into benzoin acrylate being 89%.

EXAMPLES 3 TO 7

Acrylate esters were prepared from several hindred alcohols followingthe same procedure as described in Example 1. The alcohols used werephenol, 2,6-di-t-butyl-4-methylphenol, diphenylmethanol,triphenylmethanol and 2,6-dimethyl-4-heptanol and the results obtainedare shown in the following table where "Yield of Product" indicates theyield of acrylate ester based on starting alcohol.

                  TABLE                                                           ______________________________________                                                                          Yield of                                                             Reaction Product                                     Example   Starting Alcohol                                                                             Time (h) (%)                                         ______________________________________                                        3         Phenol         1        96                                          4         2,6-di-t-butyl-4-                                                                            2        73                                                    methylphenol                                                        5         Diphenylmethanol                                                                             1        98                                          6         Triphenylmethanol                                                                            1        72                                          7         2,6-Dimethyl-4-                                                                              1        95                                                    heptanol                                                            ______________________________________                                    

EXAMPLE 8

This example demonstrates a process broadly similar to Example 1 butusing dichloromethane instead of toluene.

Benzoin (57 g), phosphorus pentoxide (1.7 g) and triethylamine (59.9 g)were stirred in dry dichloromethane (200 cm³) and heated to reflux afterwhich 3-chloropripionyl chloride (42.8 g) was added dropwise over 40min. After addition was complete the reaction was continued for afurther 60 min before being allowed to cool to ambient and ater (50 cm³)added with stirring to dissolve the triethylammonium chloride. Theaqueous phase was separated and the organic extract washed with water(50 cm³). The combined aqueous layers were then backwashed withdichloromethane (30 g).

The combined organic phases were returned to the reaction flask andwater was removed by distillation of the azeotrope with dichloromethane.The solvent was removed by distillation to give 70 g (97.9%) of a crudedark yellow product. Recrystallisation yielded 58.6 g of a fine yellowpowder.

Because dichloromethane can result in halo carbon residues in the endproduct in trace amounts, and because its use necessitates extensiverecovery procedures, this process is much less satisfactory than theprocess of the preceding examples. It is significant that althoughtoluene might have been expected to be a less efficient solvent in thereaction, the yield in example 1 is substantially the same as in example8 using dichloromethane, and thus the invention has the advantage ofgiving results using toluene that are as good as can be obtained usingdichloromethane, combined with the avoidance of the disadvantages ofhalo carbons.

We claim:
 1. A process for making a vinyl ester of an alcohol byreaction of the alcohol with a 3-haloalkyl acid halide in a liquidreaction medium in which the alcohol is dissolved and through which ahydrogen halide acceptor is distributed, characterised in that theliquid reaction medium is anhydrous and comprises aprotic solvent andthe reaction temperature is at least 20° C.
 2. A process according toclaim 1 in which the reaction temperature is at least 40° C.
 3. Aprocess according to claim 1 in which the reaction medium is free ofhalo carbon and the aprotic solvent is a hydrocarbon solvent.
 4. Aprocess according to claim 1 in which the reaction medium includes awater scavenger.
 5. A process according to claim 1 in which the reactionmedium includes phosphorous pentoxide as a water scavenger.
 6. A processaccording to claim 1 in which the reaction temperature and the aproticsolvent are such that the alcohol has a solbility of at least 10% byweight in the solvent at the reaction temperature (based on the weightof alcohol and aprotic solvent).
 7. A process according to claim 1 inwhich the alcohol is selected from cyclic alcohols, tertiary alcohols,and primary or secondary alcohols substituted by at least one aliphatic,aromatic or heterocyclic group that comprises a tertiary carbonatom or aring of at least five atoms wherein the tertiary carbon atom or the ringis connected to the primary or secondary carbon of the primary orsecondary alcohol by a direct bond or by a chain of up to three atoms.8. A process according to claim 7 in which the alcohol is benzoin.
 9. Aprocess according to claim 1 in which the hydrogen halide acceptor isdissolved in the liquid reaction medium and is a tertiary amine.
 10. Aprocess according to claim 1 in which the 3-haloalkyl acid halide is3-halo propionyl halide where each of the halogen atoms is individuallyselected from chlorine and bromine.
 11. A process according to claim 1for making benzoin acrylate comprising reacting 1 mole benzoin at 40° to80° C. with 0.8 to 2 moles 3-chloro or 3-bromo propionyl chloride orbromide while dissolved in an anhydrous reaction medium that is free ofhalo carbon and that comprises a hydrocarbon solvent and a tertiaryamine hydrogen halide acceptor.